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γ-Secretase: proteasome of the membrane?

Abstract

γ-Secretase — a protease that cleaves within the membrane — was first recognized for its role in the production of amyloidogenic Aβ peptides, but was subsequently found to mediate Notch signalling by releasing the Notch-receptor intracellular domain. Many other γ-secretase substrates have recently been identified, which indicates a broader biological function for this unusual protease. Emerging evidence implies that whereas some intracellular cleavage products of γ-secretase function as signalling molecules, others might simply be intermediates that are destined for degradation.

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Figure 1: The γ-secretase complex and its role in the intramembrane proteolysis of Notch and amyloid precursor protein.
Figure 2: The 26S proteasome and the γ-secretase complex: analogous roles?

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Acknowledgements

We would like to thank the organizers and participants of the Horizon Symposium that triggered this perpective article and, specifically, Bill Parks for reading and commenting on the manuscript.

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Correspondence to Raphael Kopan.

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DATABASES

Flybase

Ci

Swiss-Prot

APP

CD44

DCC

E-cadherin

ERBB4

FE65

F-spondin

Jagged

matrilysin

N-cadherin

Notch

presenilin

S2P

SREBP

syndecan-3

TACE

TIP60

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Kopan, R., Ilagan, M. γ-Secretase: proteasome of the membrane?. Nat Rev Mol Cell Biol 5, 499–504 (2004). https://doi.org/10.1038/nrm1406

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